Preparation of phthalanes

ABSTRACT

Citalopram and other phthalanes are made by reacting a salt of a compound of formula (II) where R 1  is halogen and R 2  is halogen, trifluoromethyl, cyano or R—CO— where R is a C 1-4  alkyl group, with cuprous cyanide.

[0001] This invention relates to a process for the preparation ofcertain phthalanes, particularly but not exclusively citalopram.

[0002] The antidepressant drug citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,has the formula:

[0003] GB 1526331 describes citalopram and other closely similarphthalanes of formula:

[0004] wherein R¹ and R² each represents halogen, a trifluoromethylgroup, a cyano group or R—CO— wherein R is an alcyl radical with from 1to 4 carbon atoms, and acid addition salts thereof with pharmaceuticallyacceptable acids.

[0005] GB 1526331 describes a number of processes for making citalopram,among which is a process in which a compound of formula I in which R¹ isbromine and R² is fluorine, is reacted with cuprous cyanide in an inertorganic solvent to obtain a compound of formula II in which R¹ is acyano group, i.e. to obtain citalopram. This process is particularlydescribed in Example 3 of GB 1526331 where the yellow oil1-(4′-fluorophenyl)-5-bromophthalane (free base) and cuprous cyanide arerefluxed in dimethyl formamide. Dimethyl formamide dissolves thebromophthalane. The citalopram so formed is crystallised out by pouringthe reaction mixture into an aqueous solution of sodium cyanide.

[0006] We have investigated this process and have found that it isdifficult to carry out and generally gives only a low yield. We havetried the same process but without any solvent, and whilst the reactionconversion is good, it is very difficult to isolate pure whitecitalopram product

[0007] We have now found a way in which these difficulties can bereduced or overcome.

[0008] According to one aspect of the present invention, there isprovided a process for the preparation of a phthalane of formula II inwhich R¹ is cyano and R² is as defined for formula II above, wherein asalt of a compound of formula II in which R¹ is halogen, is reacted withcuprous cyanide.

[0009] The process is especially useful for making citalopram in whichcase R¹ in the compound of formula II is initially bromine, chlorine oriodine, and R² is fluorine. Other phthalanes can also be made.

[0010] In the process of the invention, we prefer to use the oxalatesalt, but other salts can equally be used. For example, the fumarate,acetate, maleate, mesylate, citrate, lactate, tartrate, besylate,tosylate, mandelate, benzoate, salicylate and other organic acid salts.

[0011] According to a further preferred feature of the invention, thesalt is reacted with the cuprous cyanide as a suspension in an organicliquid. There are many possible such liquids, as will be clear to thoseskilled in the art. We prefer to use diglyme but other possible organicliquids include sulfolane, dimethylsulfoxide, N-methyl pyrrolidone,tetraglyme, ethylene glycol.

[0012] The reaction is effected under heat over a period of time. Theexact conditions will depend on the organic liquid and, to a lesserextent, the salt used. The reaction is preferably conducted under aninert atmosphere, e.g. nitrogen. By way of example, we have found thatin the case of the oxalate salt and using diglyme as the organic liquid,the suspension is preferably heated at 150-155° C for about three hours.More generally, the time of heating will be from 1 to 5 hours at orbelow the reflux temperature of the organic liquid.

[0013] At the end of the reaction, citalopram is recovered from thereaction mixture by any suitable means. We have found that washing theorganic liquid with an aqueous base and then extracting the citalopraminto an aqueous acid solution is satisfactory. Upon neutralisation ofthe acid solution, the citalopram precipitates out and can berecrystallised as desired. Since citalopram is normally used in the formof its hydrobromide salt, conversion thereto is preferably effected inthe usual way.

[0014] In the above recovery procedure, we prefer to use an aqueoussolution of ethylene diamine as the base, but other bases can be usedsuch as ammonia, monomethylamine, dimethylamine, other amines, andalkali metal hydroxides. The preferred aqueous acid solution is anorganic acid solution. We prefer to use acetic acid but other acids canbe used such as hydrochloric acid, sulphuric acid, phosphoric acid,formic acid and other organic and mineral acids. In order that theinvention may be more fully understood, the following Example is givenby way of illustration only.

EXAMPLE

[0015] Bromophthalane oxalate 100 g and cuprous cyanide 35 g aresuspended in diglyme 500 ml and heated under a blanket of nitrogen to atemperature of 150-155° C. and maintained for 3 hours. The reaction massis then cooled to 50° C. and 100 ml of a 50% aqueous solution ofethylene diamine is added. The lower aqueous layer is drained off. Theorganic layer is diluted with toluene 500 ml and further washed withethylene diamine solution followed by 5% EDTA solution. The product isextracted into 10% solution of acetic acid 150 ml. Under vigorousstirring, 25% aqueous ammonia solution is then introduced into theacetic acid extract to ensure complete neutralization of the acid. Theproduct which precipitates out is filtered. The crude product is thencrystallized from n-hexane. The purified citalopram base is then takenin ethyl acetate or isopropyl alcohol, water and aqueous hydrobromicacid is added. The product is filtered and dried in a vacuum oven toobtain 35 g of citalopram hydrobromide.

1 A process for the preparation of a phthalane of formula

wherein R² is halogen, trifluoromethyl cyano or R—CO— where R is analkyl radical having from 1 to 4 carbon atoms, and acid addition saltsthereof, which comprises reacting a salt of a compound of formula

in which R¹ is halogen and R² is as defined above, with cuprous cyanide.2 A process according to claim 1, wherein R² is fluorine. 3 A processaccording to claim 1 or 2, wherein said salt is an organic acid salt. 4A process according to claim 3, wherein the salt of formula II is theoxalate. 5 A process according to claim 3, wherein the salt of formulaII is the fumarate, acetate, maleate, mesylate, citrate, lactate,tartrate, besylate, tosylate, madelate, benzoate or salicylate. 6 Aprocess according to any of claims 1 to 5, wherein the salt of formulaII is reacted with the cuprous cyanide in an organic liquid. 7 A processaccording to claim 6, wherein the organic liquid is diglyme. 8 A processaccording to claim 6, wherein the organic liquid is sulfolane,dimethylsulfoxide, N-methyl pyrrolidone, tetraglyme or ethylene glycol.9 A process according to any of claims 1 to 8, wherein the reaction isconducted under heating in an inert atmosphere. 10 A process accordingto any of claims 1 to 9, wherein at the end of the reaction, thereaction mixture is washed with an aqueous base, and the phthalane isextracted from the wash liquid into an aqueous acid solution. 11 Aprocess according to claim 10, wherein the base is ammonia, an amine, oran alkali metal hydroxide, and the acid is an organic acid. 12 A processaccording to claim 9 or 10, wherein the aqueous acid solution extract isneutralised to precipitate the phthalane. 13 A process according to anyof claims 1 to 12, wherein the phthalane of formula III is citalopram.14 process according to any of claims 1 to 13, wherein the phthalane offormula III is converted to a salt thereof.